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Antioxidants
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Cellular Redox Homeostasis
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Cellular Redox Homeostasis

A special issue of Antioxidants (ISSN 2076-3921).

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 27989

Special Issue Editors

Prof. Dr. Edward E. Schmidt

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Guest Editor
1. Department of Microbiology and Cell Biology, Montana State University, Bozeman, MT, USA
2. Laboratory of Redox Biology, Departments of Pharmacology and Physiology, Hungarian Veterinary Medical University, Budapest, Hungary
Interests: gene regulation; cell and organismal physiology; genetics; embryology; redox biology; biochemistry; metabolism; mouse models
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Hun-Taeg Chung

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Guest Editor
School of Biological Sciences, University of Ulsan, Ulsan, Korea
Prof. Dr. Volkan Sayin

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Guest Editor
Department of Surgery at Institute of Clinical Sciences, Gothenburg, Sweden

Special Issue Information

Dear Colleagues,

The health of cells and organisms depends on the maintenance of correctly balanced cytosolic and organellar redox states. The major cellular players in maintaining this balance are (1) the glutathione and thioredoxin systems; (2) the NADPH-regenerating systems that provide reducing power to these systems; and (3) the glutathione- or thioredoxin-dependent reductase enzymes, including peroxidases and others, that ultimately utilize this reducing power to eliminate oxidants or repair oxidative damage. Cells invest considerable resources into these systems, and deficiencies of these systems underlie many diseases. Diverse pathological states, both within experimental models and in the clinic, have been shown to respond favorably to supplemental antioxidant treatments, and a rich body of literature documents the therapeutic values of synthetic supplemental antioxidants, such as N-acetylcysteine or bardoxolone methyl, as well as of natural supplemental antioxidants, such as Vitamins C and E, sulforaphane, and others. Ongoing advances are being made in understanding the pathways that are affected and the mechanisms of action of supplemental antioxidants. More recently, however, studies have revealed a ‘dark side’ to some uses of supplemental antioxidants, wherein their protective benefits might be hijacked by oxidatively susceptible cancer cells, their activities might blunt endogenous defenses, or their metabolism might detrimentally increase stress on already stressed systems. Accordingly, comprehensive studies of the cancer genome have revealed that mutations that activate the endogenous oxidative stress response are selected in multiple types of cancer. This Special Issue aims to present papers that address the basic biology of cellular redox homeostasis and papers that provide a diverse balanced presentation of both the beneficial and detrimental impacts that antioxidant supplements can have in the context of disease states. The editors of this Special Issue welcome submissions of primary research papers, timely reviews, and visionary perspective or retrospective analyses within this domain.

Prof. Dr. Edward E. Schmidt
Prof. Dr. Hun-Taeg Chung
Prof. Dr. Volkan Sayin
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antioxidants is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (8 papers)

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17 pages, 4308 KiB  
Article
Supplemental Ascorbate Diminishes DNA Damage Yet Depletes Glutathione and Increases Acute Liver Failure in a Mouse Model of Hepatic Antioxidant System Disruption
by Colin G. Miller, Jean A. Kundert, Justin R. Prigge, Julie A. Amato, Allison E. Perez, Lucia Coppo, Gabrielle N. Rizzo, Michael P. Kavanaugh, David J. Orlicky, Colin T. Shearn and Edward E. Schmidt
Antioxidants 2021, 10(3), 359; https://doi.org/10.3390/antiox10030359 - 27 Feb 2021
Cited by 2 | Viewed by 3086
Abstract
Cellular oxidants are primarily managed by the thioredoxin reductase-1 (TrxR1)- and glutathione reductase (Gsr)-driven antioxidant systems. In mice having hepatocyte-specific co-disruption of TrxR1 and Gsr (TrxR1/Gsr-null livers), methionine catabolism sustains hepatic levels of reduced glutathione (GSH). Although most mice with TrxR1/Gsr-null livers exhibit [...] Read more.
Cellular oxidants are primarily managed by the thioredoxin reductase-1 (TrxR1)- and glutathione reductase (Gsr)-driven antioxidant systems. In mice having hepatocyte-specific co-disruption of TrxR1 and Gsr (TrxR1/Gsr-null livers), methionine catabolism sustains hepatic levels of reduced glutathione (GSH). Although most mice with TrxR1/Gsr-null livers exhibit long-term survival, ~25% die from spontaneous liver failure between 4- and 7-weeks of age. Here we tested whether liver failure was ameliorated by ascorbate supplementation. Following ascorbate, dehydroascorbate, or mock treatment, we assessed survival, liver histology, or hepatic redox markers including GSH and GSSG, redox enzyme activities, and oxidative damage markers. Unexpectedly, rather than providing protection, ascorbate (5 mg/mL, drinking water) increased the death-rate to 43%. In adults, ascorbate (4 mg/g × 3 days i.p.) caused hepatocyte necrosis and loss of hepatic GSH in TrxR1/Gsr-null livers but not in wildtype controls. Dehydroascorbate (0.3 mg/g i.p.) also depleted hepatic GSH in TrxR1/Gsr-null livers, whereas GSH levels were not significantly affected by either treatment in wildtype livers. Curiously, however, despite depleting GSH, ascorbate treatment diminished basal DNA damage and oxidative stress markers in TrxR1/Gsr-null livers. This suggests that, although ascorbate supplementation can prevent oxidative damage, it also can deplete GSH and compromise already stressed livers. Full article
(This article belongs to the Special Issue Cellular Redox Homeostasis)
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14 pages, 3689 KiB  
Article
Antioxidants Promote Intestinal Tumor Progression in Mice
by Zhiyuan V. Zou, Kristell Le Gal, Ahmed E. El Zowalaty, Lara E. Pehlivanoglu, Viktor Garellick, Nadia Gul, Mohamed X. Ibrahim, Per-Olof Bergh, Marcus Henricsson, Clotilde Wiel, Levent M. Akyürek, Martin O. Bergo, Volkan I. Sayin and Per Lindahl
Antioxidants 2021, 10(2), 241; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10020241 - 04 Feb 2021
Cited by 14 | Viewed by 3245
Abstract
Dietary antioxidants and supplements are widely used to protect against cancer, even though it is now clear that antioxidants can promote tumor progression by helping cancer cells to overcome barriers of oxidative stress. Although recent studies have, in great detail, explored the role [...] Read more.
Dietary antioxidants and supplements are widely used to protect against cancer, even though it is now clear that antioxidants can promote tumor progression by helping cancer cells to overcome barriers of oxidative stress. Although recent studies have, in great detail, explored the role of antioxidants in lung and skin tumors driven by RAS and RAF mutations, little is known about the impact of antioxidant supplementation on other cancers, including Wnt-driven tumors originating from the gut. Here, we show that supplementation with the antioxidants N-acetylcysteine (NAC) and vitamin E promotes intestinal tumor progression in the ApcMin mouse model for familial adenomatous polyposis, a hereditary form of colorectal cancer, driven by Wnt signaling. Both antioxidants increased tumor size in early neoplasias and tumor grades in more advanced lesions without any impact on tumor initiation. Importantly, NAC treatment accelerated tumor progression at plasma concentrations comparable to those obtained in human subjects after prescription doses of the drug. These results demonstrate that antioxidants play an important role in the progression of intestinal tumors, which may have implications for patients with or predisposed to colorectal cancer. Full article
(This article belongs to the Special Issue Cellular Redox Homeostasis)
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13 pages, 3827 KiB  
Article
Mitochondria-Targeted Antioxidants MitoQ and MitoTEMPO Do Not Influence BRAF-Driven Malignant Melanoma and KRAS-Driven Lung Cancer Progression in Mice
by Kristell Le Gal, Clotilde Wiel, Mohamed X. Ibrahim, Marcus Henricsson, Volkan I. Sayin and Martin O. Bergo
Antioxidants 2021, 10(2), 163; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10020163 - 22 Jan 2021
Cited by 14 | Viewed by 3695
Abstract
Cancer cells produce high levels of mitochondria-associated reactive oxygen species (ROS) that can damage macromolecules, but also promote cell signaling and proliferation. Therefore, mitochondria-targeted antioxidants have been suggested to be useful in anti-cancer therapy, but no studies have convincingly addressed this question. Here, [...] Read more.
Cancer cells produce high levels of mitochondria-associated reactive oxygen species (ROS) that can damage macromolecules, but also promote cell signaling and proliferation. Therefore, mitochondria-targeted antioxidants have been suggested to be useful in anti-cancer therapy, but no studies have convincingly addressed this question. Here, we administered the mitochondria-targeted antioxidants MitoQ and MitoTEMPO to mice with BRAF-induced malignant melanoma and KRAS-induced lung cancer, and found that these compounds had no impact on the number of primary tumors and metastases; and did not influence mitochondrial and nuclear DNA damage levels. Moreover, MitoQ and MitoTEMPO did not influence proliferation of human melanoma and lung cancer cell lines. MitoQ and its control substance dTPP, but not MitoTEMPO, increased glycolytic rates and reduced respiration in melanoma cells; whereas only dTPP produced this effect in lung cancer cells. Our results do not support the use of mitochondria-targeted antioxidants for anti-cancer monotherapy, at least not in malignant melanoma and lung cancer. Full article
(This article belongs to the Special Issue Cellular Redox Homeostasis)
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12 pages, 1272 KiB  
Article
Qualitative Differences in Protection of PTP1B Activity by the Reductive Trx1 or TRP14 Enzyme Systems upon Oxidative Challenges with Polysulfides or H2O2 Together with Bicarbonate
by Markus Dagnell, Qing Cheng and Elias S.J. Arnér
Antioxidants 2021, 10(1), 111; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10010111 - 14 Jan 2021
Cited by 7 | Viewed by 2080
Abstract
Protein tyrosine phosphatases (PTPs) can be regulated by several redox-dependent mechanisms and control growth factor-activated receptor tyrosine kinase phosphorylation cascades. Reversible oxidation of PTPs is counteracted by reductive enzymes, including thioredoxin (Trx) and Trx-related protein of 14 kDa (TRP14), keeping PTPs in their [...] Read more.
Protein tyrosine phosphatases (PTPs) can be regulated by several redox-dependent mechanisms and control growth factor-activated receptor tyrosine kinase phosphorylation cascades. Reversible oxidation of PTPs is counteracted by reductive enzymes, including thioredoxin (Trx) and Trx-related protein of 14 kDa (TRP14), keeping PTPs in their reduced active states. Different modes of oxidative inactivation of PTPs concomitant with assessment of activating reduction have been little studied in direct comparative analyses. Determining PTP1B activities, we here compared the potency of inactivation by bicarbonate-assisted oxidation using H2O2 with that of polysulfide-mediated inactivation. Inactivation of pure PTP1B was about three times more efficient with polysulfides as compared to the combination of bicarbonate and H2O2. Bicarbonate alone had no effect on PTP1B, neither with nor without a combination with polysulfides, thus strengthening the notion that bicarbonate-assisted H2O2-mediated inactivation of PTP1B involves formation of peroxymonocarbonate. Furthermore, PTP1B was potently protected from polysulfide-mediated inactivation by either TRP14 or Trx1, in contrast to the inactivation by bicarbonate and H2O2. Comparing reductive activation of polysulfide-inactivated PTP1B with that of bicarbonate- and H2O2-treated enzyme, we found Trx1 to be more potent in reactivation than TRP14. Altogether we conclude that inactivation of PTP1B by polysulfides displays striking qualitative differences compared to that by H2O2 together with bicarbonate, also with regard to maintenance of PTP1B activity by either Trx1 or TRP14. Full article
(This article belongs to the Special Issue Cellular Redox Homeostasis)
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12 pages, 3096 KiB  
Article
Xenopus gpx3 Mediates Posterior Development by Regulating Cell Death during Embryogenesis
by Hongchan Lee, Tayaba Ismail, Youni Kim, Shinhyeok Chae, Hong-Yeoul Ryu, Dong-Seok Lee, Taeg Kyu Kwon, Tae Joo Park, Taejoon Kwon and Hyun-Shik Lee
Antioxidants 2020, 9(12), 1265; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9121265 - 12 Dec 2020
Cited by 6 | Viewed by 2759
Abstract
Glutathione peroxidase 3 (GPx3) belongs to the glutathione peroxidase family of selenoproteins and is a key antioxidant enzyme in multicellular organisms against oxidative damage. Downregulation of GPx3 affects tumor progression and metastasis and is associated with liver and heart disease. However, the physiological [...] Read more.
Glutathione peroxidase 3 (GPx3) belongs to the glutathione peroxidase family of selenoproteins and is a key antioxidant enzyme in multicellular organisms against oxidative damage. Downregulation of GPx3 affects tumor progression and metastasis and is associated with liver and heart disease. However, the physiological significance of GPx3 in vertebrate embryonic development remains poorly understood. The current study aimed to investigate the functional roles of gpx3 during embryogenesis. To this end, we determined gpx3’s spatiotemporal expression using Xenopus laevis as a model organism. Using reverse transcription polymerase chain reaction (RT-PCR), we demonstrated the zygotic nature of this gene. Interestingly, the expression of gpx3 enhanced during the tailbud stage of development, and whole mount in situ hybridization (WISH) analysis revealed gpx3 localization in prospective tail region of developing embryo. gpx3 knockdown using antisense morpholino oligonucleotides (MOs) resulted in short post-anal tails, and these malformed tails were significantly rescued by glutathione peroxidase mimic ebselen. The gene expression analysis indicated that gpx3 knockdown significantly altered the expression of genes associated with Wnt, Notch, and bone morphogenetic protein (BMP) signaling pathways involved in tailbud development. Moreover, RNA sequencing identified that gpx3 plays a role in regulation of cell death in the developing embryo. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and phospho-histone 3 (PH3) staining confirmed the association of gpx3 knockdown with increased cell death and decreased cell proliferation in tail region of developing embryos, establishing the involvement of gpx3 in tailbud development by regulating the cell death. Furthermore, these findings are inter-related with increased reactive oxygen species (ROS) levels in gpx3 knockdown embryos, as measured by using a redox-sensitive fluorescent probe HyPer. Taken together, our results suggest that gpx3 plays a critical role in posterior embryonic development by regulating cell death and proliferation during vertebrate embryogenesis. Full article
(This article belongs to the Special Issue Cellular Redox Homeostasis)
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12 pages, 1675 KiB  
Article
N-Acetylcysteine as Modulator of the Essential Trace Elements Copper and Zinc
by Theresa Wolfram, Maria Schwarz, Michaela Reuß, Kristina Lossow, Mario Ost, Susanne Klaus, Tanja Schwerdtle and Anna P. Kipp
Antioxidants 2020, 9(11), 1117; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9111117 - 12 Nov 2020
Cited by 12 | Viewed by 5733
Abstract
N-acetylcysteine (NAC) is a frequently prescribed drug and known for its metal chelating capability. However, to date it is not well characterized whether NAC intake affects the homeostasis of essential trace elements. As a precursor of glutathione (GSH), NAC also has the potential [...] Read more.
N-acetylcysteine (NAC) is a frequently prescribed drug and known for its metal chelating capability. However, to date it is not well characterized whether NAC intake affects the homeostasis of essential trace elements. As a precursor of glutathione (GSH), NAC also has the potential to modulate the cellular redox homeostasis. Thus, we aimed to analyze effects of acute and chronic NAC treatment on the homeostasis of copper (Cu) and zinc (Zn) and on the activity of the redox-sensitive transcription factor Nrf2. Cells were exposed to 1 mM NAC and were co-treated with 50 μM Cu or Zn. We showed that NAC treatment reduced the cellular concentration of Zn and Cu. In addition, NAC inhibited the Zn-induced Nrf2 activation and limited the concomitant upregulation of cellular GSH concentrations. In contrast, mice chronically received NAC via drinking water (1 g NAC/100 mL). Cu and Zn concentrations were decreased in liver and spleen. In the duodenum, NQO1, TXNRD, and SOD activities were upregulated by NAC. All of them can be induced by Nrf2, thus indicating a putative Nrf2 activation. Overall, NAC modulates the homeostasis of Cu and Zn both in vitro and in vivo and accordingly affects the cellular redox balance. Full article
(This article belongs to the Special Issue Cellular Redox Homeostasis)
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16 pages, 12435 KiB  
Article
Docosahexaenoic Acid Induces Expression of NAD(P)H: Quinone Oxidoreductase and Heme Oxygenase-1 through Activation of Nrf2 in Cerulein-Stimulated Pancreatic Acinar Cells
by Yu Jin Ahn, Joo Weon Lim and Hyeyoung Kim
Antioxidants 2020, 9(11), 1084; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9111084 - 04 Nov 2020
Cited by 14 | Viewed by 2331
Abstract
Oxidative stress is a major risk factor for acute pancreatitis. Reactive oxygen species (ROS) mediate expression of inflammatory cytokines such as interleukin-6 (IL-6) which reflects the severity of acute pancreatitis. The nuclear factor erythroid-2-related factor 2 (Nrf2) pathway is activated to induce the [...] Read more.
Oxidative stress is a major risk factor for acute pancreatitis. Reactive oxygen species (ROS) mediate expression of inflammatory cytokines such as interleukin-6 (IL-6) which reflects the severity of acute pancreatitis. The nuclear factor erythroid-2-related factor 2 (Nrf2) pathway is activated to induce the expression of antioxidant enzymes such as NAD(P)H: quinone oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1) as a cytoprotective response to oxidative stress. In addition, binding of Kelch-like ECH-associated protein 1 (Keap1) to Nrf2 promotes degradation of Nrf2. Docosahexaenoic acid (DHA)—an omega-3 fatty acid—exerts anti-inflammatory and antioxidant effects. Oxidized omega-3 fatty acids react with Keap1 to induce Nrf2-regulated gene expression. In this study, we investigated whether DHA reduces ROS levels and inhibits IL-6 expression via Nrf2 signaling in pancreatic acinar (AR42J) cells stimulated with cerulein, as an in vitro model of acute pancreatitis. The cells were pretreated with or without DHA for 1 h and treated with cerulein (10−8 M) for 1 (ROS levels, protein levels of NQO1, HO-1, pNrf2, Nrf2, and Keap1), 6 (IL-6 mRNA expression), and 24 h (IL-6 protein level in the medium). Our results showed that DHA upregulates the expression of NQO1 and HO-1 in cerulein-stimulated AR42J cells by promoting phosphorylation and nuclear translocation of Nrf2. DHA increased interaction between Keap1 and Nrf2 in AR42J cells, which may increase Nrf2 activity by inhibiting Keap1-mediated sequestration of Nrf2. In addition, DHA-induced expression of NQO1 and HO-1 is related to reduction of ROS and IL-6 levels in cerulein-stimulated AR42J cells. In conclusion, DHA inhibits ROS-mediated IL-6 expression by upregulating Nrf2-mediated expression of NQO1 and HO-1 in cerulein-stimulated pancreatic acinar cells. DHA may exert positive modulatory effects on acute pancreatitis by inhibiting oxidative stress and inflammatory cytokine production by activating Nrf2 signaling in pancreatic acinar cells. Full article
(This article belongs to the Special Issue Cellular Redox Homeostasis)
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7 pages, 593 KiB  
Perspective
Cellular Redox Homeostasis
by Kristell Le Gal, Edward E. Schmidt and Volkan I. Sayin
Antioxidants 2021, 10(9), 1377; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10091377 - 28 Aug 2021
Cited by 41 | Viewed by 4161
Abstract
Cellular redox homeostasis is an essential and dynamic process that ensures the balance between reducing and oxidizing reactions within cells and regulates a plethora of biological responses and events. The study of these biochemical reactions has proven difficult over time, but recent technical [...] Read more.
Cellular redox homeostasis is an essential and dynamic process that ensures the balance between reducing and oxidizing reactions within cells and regulates a plethora of biological responses and events. The study of these biochemical reactions has proven difficult over time, but recent technical and methodological developments have contributed to the rapid growth of the redox field and to our understanding of its importance in biology. The aim of this short review is to give the reader an overall understanding of redox regulation in the areas of cellular signaling, development, and disease, as well as to introduce some recent discoveries in those fields. Full article
(This article belongs to the Special Issue Cellular Redox Homeostasis)
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